This application examines the role of hormone metabolizing enzymes in maintaining extra and intra-cellular hormone concentrations. These are very important in determining the biological impact of hormones in health and disease. Hormone metabolizing enzymes not only degrade hormones but in some cases convert them from an inactive to an active form. The class of hormones that are being studied are peptides and thyroid hormones. The peptide hormone that will be focused on is thyrotropin releasing hormone (TRH). TRH is not only a major regulator of thyroid function but also acts in the brain to regulate temperature, gastrointestinal function, and blood pressure regulation. Certain enzymes that degrade TRH also act on other peptides including substance P, neurotensin, and luteinizing hormone releasing hormone (LHRH). In the proposed research, modal systems will be employed to define the specific enzymes involved in hormone metabolism and, to identify drugs and other compounds that inhibit enzymes, and to quantitate the role of specific enzymes in hormone degradation. Hormone degrading enzymes and hormone concentrations are quite different during development as compared to the adult. This may be partly related to the fact that the placenta metabolizes hormones made in the thyroid (thyroid hormones) or the pancreatic islets and GI tract (TRH). Therefore the placenta as well as other tissues will be studied to determine how they affect hormone levels and how these levels affect hormone action.